Three potentially useful iron chelating compounds are at different stages of drug development in our laboratories. Cholylhydroxamic acid is an orally absorbed specific iron chelator which appears to participate in the enterohepatic circulation as a bile acid analogue leading to an increase in fecal iron excretion of 564 micrograms/kg/dy in the hypertransfused rat (vs. 472 micrograms/kg/dy with desferrioxamine). This compound is now undergoing extensive animal toxicity evaluation prior to consideration of trials in humans. Rhodotorulic acid has been identified in hypertransfused rats as a specific iron chelator when administered parenterally. Studies in patients with beta-thalassemia major comparing the infusion of 25 mg/kg over a 2-hour period with the infusion of a similar dose of desferrioxiamine have shown that rhodotorulic acid leads to an average increased urinary excretion of 50 mg of iron per day. Desferrioxamine led to the excretion of 43 mg of iron per day in the same 5 patients. Studies are under way in dogs to develop rhodotorulic acid as intramuscular preparation which will peak slowly rather than being eliminated within 2 hours as occurs with desferrioxamine. These studies are being undertaken with hopes of initiating a clinical trial in the near future. 2,3-Dihydroxybenzoic acid is undergoing a year long double-blind evaluation in 15 patients with beta-thalassemia major. This study, carried out in collaboration with the Transfusion Clinic at New York Hospital, includes an evaluation of drug toxicity and will enable one to compare parameters reflecting iron overload in two comparable groups of parients, one receiving placebo, the other receiving 2,3-dihydroxybenzoic acid. BIBLIOGRAPHIC REFERENCES: Graziano JH, Cerami A: Chelation therapy for the treatment of thalassemia. Sem. Hematol. 14: 127-134, 1977. Cerami A: The development of new drugs for genetic diseases. Stadler Symp. 8, in press 1976.